Diabetes
How is Type I diabetes mellitus diagnosed?
-Diagnosed usually in children and young adults. -Blood glucose >125mg/dL after 8hr fast. Can also do random non-fasting post-prandial (2hrs after food ingestion) >200mg/dL. -An HgA1C test to show avg blood sugar for past 3 months >6.5% DCCT units (>48mmol/mol) -An antibody test to see if type I or type II => -Anti-islet => 70-90% sensitivity -Anti-insulin => 50-70% sensitivity -Glutamic acid decarboxylase => 70-90% sensitivity -Insulin-like antigen => 55-77% specificity
What are symptoms of Type I Diabetes Mellitus?
-Frequent Urination = poly urea -Increased thirst = polydipsia -Feeling drowsy or sleepy -Vision changes (things look blurry) -Increased hunger = polyphagia -Weight loss
What are the symptoms of type II diabetes?
-Frequent urination = poly urea -increased thirst = polydipsia -feeling drowsy or sleepy -increase hunger = polyphagia -slow or improper healing of cuts and bruises -tingling, pain, or numbness in hands and feet -blurry vision -hyperglycemia
What are risk factors of Type I?
-HLA-DQ and HLA -DR = 2 loci with strongest genetic risk factors, predisposes people to Type I. HLA= makes MHC class II genes. Mutations in this cause autoimmunity due to MHC presenting wrong antigens. -CTLA4 = molecule in immune system that deactivates T-cells (inhibitory switch, turns off immune system) => in type I mutation in this gene overstimulated T-cells causing autoimmunity.
How is type II diabetes mellitus diagnosed?
-HgA1C >6.5% (IFCC >49mmol/mol) -fasting blood glucose >125mg/dL -2 hr postprandial and random blood glucose >200mg/dL
What hormones are involved in blood-glucose homeostasis?
-Insulin => released from pancreatic beta-cells in response to high blood glucose -Glucagon => released from pancreatic alpha-cells in response to low blood glucose
What is the treatment for type II diabetes mellitus?
-weight loss, nutrition, insulin pump/pen, metformin, thiazoldinedione, sulfonylurea, alpha-glucosidase inhibitors
What is the range for: 1) normal fasting blood glucose ? 2) after eating ? 3) 2-3 hours after eating ?
1) 80-100 mg/dL 2) 170-200 mg/dL 3) 120-140
What are the 3 phases of Type II diabetes mellitus?
1) Obese individuals develop insulin resistance, which may precede the development of diabetes by 10 or more years. 2) Patients diagnosed with type II diabetes initially show insulin resistance with compensatory hyperinsulinemia. 3) Subsequently, beta-cell dysfunction occurs, marked by declining insulin section and worsening hyperglycemia.
What is considered pre-diabetic stage?
100-125mg/dL
What is the pre-pro insulin composed of?
A chain, B chain, signal sequence, and C-peptide/chain
A 67 year-old man was suspected of having type II diabetes during a routine physical examination. During a 1-month follow-up, his doctor ran blood work (after an overnight fast) to test for various diabetic markers. Which of the following results best fits an EARLY type II diabetic profile? (Glucose mg/dL), HgA1C (%), C-peptide (ng/ml) A) 128 mg/dL, 6.5%, 6.5 ng/ml B) 82 mg/dL, 5.4%, 2.0 ng/ml C) 225 mg/dL, 6.4%, 7.1 ng/ml D) 265 mg/dL, 7.0%, 0.7 ng/ml E) 130 mg/dL, 7.2%, 0.4 ng/ml
A) 128 mg/dL, 6.5%, 6.5 ng/ml => The onset of type-II diabetes is usually slow and gradual, characterized by increasing insulin resistance over many years. Due to waning insulin effectiveness, glucose levels begin to rise. Eventually (often years later), the pancreatic β-cells become overly dysfunctional and can no longer make adequate amounts of insulin, whereby hyperglycemia rises precipitously. An early type-II diagnosis is characterized by high levels of insulin production (measured as elevated C-peptide) as β-cells attempt to overcompensate for increasing insulin resistance. Additionally, there is minimal hyperglycemia (i.e., glucose levels are above 120 mg/dL but not substantially so) as increased insulin production struggles to maintain glucose homeostasis. Early disease may or may not have elevated hemoglobin A1c.
Type I Diabetes Mellitus
Absolute deficiency of insulin, caused by autoimmune attack on the beta cells of pancreas. Causes high blood glucose, excess glucose in urine. In type I, islets of Langerhans become infiltrated with activated B-cells and T-cells, leading to insulitis (inflammatory infiltrate of immune cells into the islets of Langerhans). Beta cells are destroyed, symptoms appear when 80-90% are gone. Insulin intervention therapy is needed.
What is Sulfonylurea and what does it do?
Another class of drugs for type II that increases insulin secretion => binds to receptor on panc cell that closes K+ channel => triggers VG Ca2+ channel to open, and insulin granules are released.
A 56-year-old woman comes to your clinic for her annual physical exam. She reports increased urinary frequency and thirst but is otherwise feeling generally well. She is obese, does not exercise, and regularly eats fried foods. A random blood glucose level is 223 mg/dL, and her hemoglobin A1c is 9.2%. A new dietary/exercise regimen is drawn up and low-dose metformin is prescribed. Which of the following is most likely to occur in this patient? A) Increased production of glucose from the liver B) Decreased production of glucose from the liver C) Decreased secretion of insulin from the pancreas D) Decreased entry of glucose into muscle cells E) Decreased speed of carbohydrate absorption from the intestines F) Increased secretion of insulin from the pancreas
B) Decreased production of glucose from the liver => Metformin is a pleiotropic agent that serves to decrease glucose levels in the blood, as a means to help diabetics maintain a healthy blood-glucose level (70-100 mg/dL). The mechanism by which metformin decreases blood-glucose levels is multifold but centers upon decreasing ATP production in a cell by reducing electron movement through Complex I of the electron-transport chain, which has a ripple-down effect of slowing gluconeogenesis, boosting insulin sensitivity, and increasing glucose uptake.
Relative or absolute lack of insulin in humans would result in which of the following reactions in the liver? A) Decreased gluconeogenesis from lactate B) Increased ketogenesis C) Increased activity of pyruvate kinase D) Increased glycogenesis E) Decreased glycogenolysis
B) Increased ketogenesis => The lack of insulin, the primary anabolic hormone in humans, would lead to overall reduction in synthetic pathways (ex: glycogenesis, lipogenesis) as well as reduced rates of glycolysis. At the same time, the lack of insulin in humans would lead to a lowering of intracellular glucose levels (since insulin works to increase glucose uptake in tissues like muscle and fat) and would correspond with a compensatory increase in glucagon, in order to activate fuel-mobilization pathways (gluconeogenesis, glycogenolysis, ketogenesis). => can't utilize glucose so body will try to compensate by doing ketogenesis
A 42-year-old man with recently diagnosed type-2 diabetes mellitus comes to the physician for a follow-up examination. Physical examination shows no abnormalities. Laboratory studies show an increased hemoglobin A1c despite patient compliance with diet and exercise recommendations. Treatment with a sulfonylurea is started. Which of the following is most likely to occur in this patient? A) Decreased speed of carbohydrate absorption from the intestines B) Decreased entry of glucose into the muscle cells C) Increased secretion of insulin from the pancreas D) Decreased secretion of insulin from the pancreas E) Decreased production of glucose from the liver
C) Increased secretion of insulin from the pancreas => Sulfonylurea drugs work to lower blood-glucose levels by increasing insulin secretion from the pancreas by binding to a cell-surface receptor that closes the ATP-sensitive K-channels in the β-cell plasma membrane. Closing ATP-sensitive K-channels depolarizes the cell membrane, which opens voltage-gated calcium channels, allowing calcium to enter the cell, leading to the exocytosis/release of secretory granules containing insulin. More insulin should lower blood-glucose levels by increasing glucose uptake.
What occurs metabolically in Type I diabetes mellitus?
Catabolic pathways activated -increased Glycogenolysis -increased Gluconeogenesis -increased Lipolysis -decreased Liver glycolysis => no insulin, glucose not utilized, body thinks it needs to make more glucose => results in hyperglycemia
A 45-year-old African American male was found unconscious at his desk and rushed to the emergency room. He has type-I diabetes and an injectable insulin pen was found at his desk. Blood tests revealed serum glucose < 20mg/dL. Which of the statements below reflects the pathogenesis of the patient's presentation? A) He is experiencing a hyperglycemic-induced coma B) Low glucagon levels due to type-I diabetes increased expression of hepatic glucokinase, resulting in increased glycogen synthesis C) Insulin overdose led to increased expression of pancreatic hexokinase, causing severe hypoglycemia D) An overdose of insulin caused severe hypoglycemia E) Low insulin levels due to type-I diabetes caused severe hypoglycemia
D) An overdose of insulin caused severe hypoglycemia => A common but dangerous side-effect with insulin injections is unintended hypoglycemia, when the glucose-to-insulin balance is skewed, so that more glucose is removed from the blood than is safe, endangering such individuals with bouts of hypoglycemia. This individual likely took an insulin injection without accompanying nutrient intake, leading to a dangerous drop in homeostatic blood-glucose levels and resulting in a hypoglycemic coma.
What are the risk factors of Type II diabetes mellitus?
Genetic = TCF7L2 gene = transcription factor involved in insulin production. Also, another transcription factor (PPARgamma) involved in fat cell differentiation (obesity). Family history. Environment = obesity. Leads to more inflammation (MCP1 increases= recruits inflammatory cells new adipocytes) which lowers insulin sensitivity.
How does autoimmunity develop as a prelude to Type I diabetes?
Genetic Component and Environmental trigger/component
How is insulin released from pancreatic beta cells?
Glucose enters pancreatic cells via GLUT2 (insulin independent). Inside cytoplasm, Glucose is converted to G6P by glucokinase (pancreatic/liver hexokinase, high Km), and now locked into glycolysis. Increase ATP [ ] in the cell causes ATP-sensitive K+ channels to close => resulting in depolarization (more +) of cell membrane. This triggers VG Ca2+ channels to open, Ca2+ comes inside cell, causing exocytosis/secretion of pre-formed insulin granules from beta cell to blood. => 1st peak of insulin secretion. 2nd phase/peak of insulin => when glucose levels stay elevated, pancreatic beta cells will make new insulin. *Bimodal release of insulin helps bring glucose down to normal physiologic [ ]
What does HgA1C indicate?
HgA is predominate form of Hg carried by RBCs. HgA1C shows glycation of glucose to HgA, which impairs RBC function. Shows glucose levels in blood for 3-4 month period (120days), because that is the avg life span of RBC.
How does pre-pro insulin become pro-insulin?
In the rough ER of pancreatic beta cell, the signal sequence is proteolytically cleaved, leaving A chain, B chain and C-peptide = Pro-insulin
What does insulin resistance mean?
Insulin protein is no longer able to exert optimal biological effect. Can be due to: -insulin molecule itself is not in the correct formation -insulin receptor not binding correctly -downstream signaling components are not as effective in transducing signal to cell -Occurs when beta cells are overworked from constantly producing a lot of insulin.
Type II Diabetes Mellitus
Insulin resistance. Characterized by combination of insulin resistance and dysfunctional beta cells in pancreas. Something wrong in insulin pathway (receptor etc.) so not enough functioning insulin. Causes high blood glucose and excess glucose in urine.
What is MHC?
Major Histocompatibility complex = in immune system => presents antigens, pieces of peptides, for body to recognize and attack. In type I, body presents wrong type of antigens/proteins, causing autoimmune response.
What is C-peptides used for?
Measure of endogenous insulin levels => 1:1 stoichiometric relationship to insulin. C-peptide has a longer half-life (20-40 min) and provides estimate of the rate of insulin production and secretion from pancreas (looking at pancreatic function etc.)
What are the chronic effects of Type I diabetes mellitus?
Microvascular => eye (retinopathy), kidney (nephropathy), Neuropathy Macrovascular => brain (increased stroke etc.), heart (increased risk of coronary heart disease), extremities (peripheral vascular disease from narrowing blood vessels = decreased blood flow)
How is pro-insulin processed to mature insulin?
Pro-insulin folds into proper conformation, transported to Golgi Apparatus/complex. Then leaves Golgi + pancreatic cell in the form of insulin vesicles/granules. Inside granules, a protease cleaves pro-insulin, removing C-peptide => resulting in biologically active insulin (composed of A chain and B chain with disulfid bonds)
What is an autoimmune disease/autoimmunity?
The immune system can't distinguish between host-self tissue and foreign things. Body attacks self.
Why does diabetic ketoacidosis occur and in which subtype of diabetes?
Type I => due to increased ketone body production (as an energy source). Drops blood pH, overwhelms blood buffering capacity. Symptoms= poly urea, polydipsia, abdominal pain, nausea, high blood glucose, high ketone levels, SOB, weakness, fatigue, confusion, fruity-smelling breath -severe case can result in loss of consciousness Treatment by replaced fluids, electrolytes, infusion with alkalinizing sol'n, and insulin
What are the metabolic changes in type II diabetes mellitus?
Uncommon to enter ketoacidosis, because in type II you still have some functioning insulin. No ketonemia Still have increased blood glucose, increased gluconeogenesis, increased lipolysis, decreased liver glycolysis.
What is GLUT2?
a facilitative glucose transporter (insulin independent) located in the plasma membrane of the liver, pancreatic, intestinal, kidney cells as well as in the portal and the hypothalamus areas.
What are hyperglycemic values of blood glucose?
above 125mg/dL (>7.8mmol/L)
What is the alpha-glucosidase inhibitor and what does it do?
another class of drugs for Type II, inhibits digestion of complex carbohydrates like starch, thus less glucose is absorbed from intestinal tract=> thus less glucose in blood.
What are hypoglycemic values of blood glucose?
below 70mg/dL (<3.3mmol/L)
What is Thiazoldinedione and what does it do?
class of drug for type II that acts at level of transcription => binds to PPARgamma and activates it = a nuclear receptor in liver, adipose, muscle => decreases/inhibits lipolysis and slows down gluconeogenesis (by decreasing free FA acids that are used used in pathway), lowers inflammation, and improves insulin sensitivity
What is ketogenesis and when does it occur?
in type I diabetes, due to lipolysis => FA in liver get converted to ketone bodies (acetoacetate, acetone and beta-hydroxybutyrate), which then gets transported to blood, tissues, brain for to make energy. PROBLEM = too many ketone bodies = blood pH drops, too acidic, get diabetic ketoacidosis in type I.
Describe insulinoma and its hallmark feature
neoplasm in pancreatic beta cells resulting in overproduction of insulin. Causes Low blood glucose levels (hypoglycemia) due to increased insulin production and High C-peptide (marker for mature insulin production). High C-peptide, High Insulin, and Hypoglycemia = hallmark features of insulinoma
What is the treatment of Type I diabetes?
no cure insulin injections (pump or self) exercise nutrition/diet
What is metformin and what does it do?
treatment for Type II diabetes mellitus. First line therapy, in class of drugs = biguanides. *Lowers blood glucose by inhibiting ComplexI of ETC => leading to drop in ATP [ ], drop in downstream effect in cell. (cell doesn't die because rest of ETC complexes function. *Inhibits gluconeogenesis (not enough energy available to make glucose due to low ATP), inhibits lipogenesis, promotes FA oxidation, increased glucose uptake, and increases insulin sensitivity.